Gastric enterochromaffin-like cell hyperplasia and neoplasia in the rat: an indirect effect of the histamine H2-receptor antagonist, BL-6341.
Toxicol Pathol
; 16(2): 273-87, 1988.
Article
em En
| MEDLINE
| ID: mdl-2903543
ABSTRACT
Oral administration of BL-6341 hydrochloride, a long-acting histamine H2-receptor antagonist, to rats for 2 years at doses of 10, 55 or 300 mg/kg/day resulted in several changes in the fundic (oxyntic) mucosa of the glandular stomach. The most significant alteration was a proliferation of argyrophil endocrine cells that was demonstrated to be enterochromaffin-like (ECL) cells. The ECL cell proliferation consisted of a continuum of changes involving diffuse hyperplasia, focal adenomatous hyperplasia, and carcinoid tumor formation at the highest dose level of 300 mg/kg. At 55 mg/kg only ECL cell hyperplasia occurred, and at the low dose of 10 mg/kg there were no remarkable proliferative changes. The reference compound, cimetidine (950 mg/kg), produced a degree of ECL cell proliferation that was slightly less, but not significantly different than, that observed with 55 mg/kg of BL-6341. Dose-related elevations of serum gastrin were observed with BL-6341, while cimetidine produced hypergastrinemia that was generally intermediate between that produced by the middle and low doses of BL-6341. The hypergastrinemia resulted from the pharmacologic inhibition of acid secretion, which is the negative feedback mechanism controlling the production of gastrin. Only the 300 mg/kg dose of BL-6341 produced a significant, sustained (24 hours) hypergastrinemia and carcinoid tumors. The chronic, sustained hypergastrinemia was considered to be the primary cause of the ECL cell carcinoid neoplasia. All genetic toxicology tests performed with BL-6341 were negative. It was concluded that the demonstrated hypergastrinemia represents an indirect, hormonal, epigenetic mechanism of tumorigenesis.
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Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
/
Estomago
Base de dados:
MEDLINE
Assunto principal:
Gastropatias
/
Neoplasias Gástricas
/
Carcinógenos
/
Tumor Carcinoide
/
Sistema Cromafim
/
Células Enterocromafins
/
Guanidinas
/
Antagonistas dos Receptores H2 da Histamina
Tipo de estudo:
Etiology_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Toxicol Pathol
Ano de publicação:
1988
Tipo de documento:
Article